The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

  • Authors:
    • Ha Thi Nguyen
    • Hong‑Quan Duong
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  • Published online on: May 9, 2018     https://doi.org/10.3892/ol.2018.8679
  • Pages: 9-18
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Abstract

Colorectal cancer (CRC) results from the progressive accumulation of multiple genetic and epigenetic aberrations within cells. The progression from colorectal adenoma to carcinoma is caused by three major pathways: Microsatellite instability, chromosomal instability and CpG island methylator phenotype. A growing body of scientific evidences suggests that CRC is a heterogeneous disease, and genetic characteristics of the tumors determine their prognostic outcome and response to targeted therapies. Early diagnosis and effective targeted therapies based on a current knowledge of the molecular characteristics of CRC are essential to the successful treatment of CRC. Therefore, the present review summarized the current understanding of the molecular characteristics of CRC, and discussed its implications for diagnosis and targeted therapy.

Introduction

Despite improvements in early detection and treatment method in recent years, colorectal cancer (CRC) remains the third most frequent and the fourth leading cause of cancer-associated mortalities worldwide (1,2). Approximately 65% of CRC cases are sporadic with no family history or apparent genetic predisposition (3). The remaining cases are familial, arising from moderately penetrant inherited susceptibility, possibly interacting with environmental factors (3,4).

CRC, like numerous other solid tumors, is a heterogeneous disease in which different subtypes may be distinguished by their specific clinical and/or molecular features. The majority of sporadic CRCs (~85%) exhibit chromosomal instability (CIN), with changes in chromosome number and structure (58). These changes include gains or losses of chromosomal segments, chromosomal rearrangements, and loss of heterozygosity (LOH), which results in gene copy number variations (CNVs) (58). These alterations affect the expression of tumor-associated genes, and/or genes that regulate cell proliferation or cell cycle checkpoints, which, in turn, may activate pathways essential for CRC initiation and progression (9,10). The remaining sporadic cases (~15%) have high-frequency microsatellite instability (MSI) phenotypes. However, hereditary CRC has two well-described forms: Familial adenomatous polyposis (FAP) (<1%) patients inherit a mutated copy of the adenomatous polyposis (APC) gene, whereas hereditary non-polyposis colorectal cancer (HNPPC, or Lynch syndrome) (1–3%) is characterized by MSI, a consequence of a defective DNA mismatch repair (MMR) system (11). The other forms of hereditary CRC include a rare syndrome called hamartomatous polyposis syndrome (<1%) and the common inherited cases caused by less penetrant inherited mutations (32%) (3).

Sequential acquisition of genetic and epigenetic alterations is well defined, and confirmed to drive the initiation and progression of adenomas to carcinomas in sporadic and inherited forms of CRC (1214). Generally, CRC formation begins with the transformation of a normal colorectal epithelium to a benign adenoma, and then progresses through the stepwise accumulation of multiple genetic and epigenetic aberrations, subsequently leading to invasive and metastatic tumors (1214). This process may take years to decades to escape the multiple regulatory layers of the cells and to fully develop (Fig. 1) (13,15). There are three major pathways associated with CRC pathogenesis, namely: CIN, MSI and CpG island methylator phenotype (CIMP) (16).

The extent to which cancer has spread at the time of diagnosis is described as its stage. Currently, CRC staging is primarily based on the tumor-nodes-metastasis (TNM) system proposed by the American Joint Committee on Cancer (17). The survival rate of patients with CRC largely depends on the stage at which tumor is first diagnosed and varies between stages. For example, the 5-year-survival rate for patients with stage I colon cancer is 93.2%, which drops to 8.1% for patients with stage IV (17). Although TNM is currently the most common CRC staging system, and an important basis to determine the treatment method and assessing prognosis, it is not a reliable tool for prediction and prognosis. Particularly, CRC patients with similar histopathology may have completely different progression and outcome depending on their genetic and epigenetic background (18). Thus, understanding the molecular pathways underlying the initiation and development of CRC is essential to identify novel molecular biomarkers for diagnosis and prognosis, thereby improving the outcome. The present review summarized the current knowledge of the genetic and epigenetic integrity, the consequences of the DNA MMR machinery associated with CRC, and the role of molecular characterization in early diagnosis and in the treatment of CRC.

Molecular basis of CRC

CIN pathway

The average rate of genomic mutation in normal human cells is estimated to be ~2.5×10−8 mutations/nucleotide/generation (19,20). However, this rate is higher in cancer cells due to the sequential accumulation of multiple mutations during cell divisions forming a so-called ‘mutator phenotype’ (21). Accordingly, mutations in MMR genes, genes that regulate cell cycle checkpoints, and/or cellular responses may elevate mutation rates to the level commonly observed in human tumors (21). The ‘mutator phenotype’ may have various manifestations, including point mutations, CIN, MSI, CIMP and LOH (21).

CIN appears to be the most common type of genetic instability in CRC, observed in 85% of adenoma-carcinoma transitions (57). CIN refers to a high rate of gains or losses of whole, or large portions of chromosomes. This leads to karyotypic variability from cell to cell that consequently forms an aneuploidy, sub-karyotypic amplification, chromosomal rearrangement, and a high frequency of LOH at tumor suppressor gene loci (5,6). In addition, CIN tumors are recognized by the accumulation of mutations in specific oncogenes, including KRAS proto-oncogene GTPase (KRAS) and B-Raf proto-oncogene serine/threonine kinase (BRAF), and tumor suppressor genes, such as APC and tumor protein p53 (TP53), thereby contributing to CRC tumorigenesis (6,10). The multistep genetic model of colorectal carcinogenesis proposed by Fearon and Vogelstein is now widely accepted, and used as a paradigm for solid tumor progression (12). According to this model, inactivation of APC occurs as the first event, followed by oncogenic KRAS mutations in the adenomatous stage, and eventually, deletion of chromosome 18q and inactivation of the tumor-suppressor gene TP53 on chromosome 17p occur during the transition to malignancy (Fig. 1) (12,2225).

Array-based comparative genomic hybridization and single nucleotide polymorphism techniques have enabled scientists to effectively determine CNVs in the entire human genome with higher resolution. Although the allelic loss of all chromosomal arms has been detected in certain tumors, its frequency varies considerably, and only a few of them are highly recurrent in CRC, including losses at chromosomal arms 1p, 5q, 8p, 17p, 18p, 18q, 20p and 22q (2631). A high-frequency allelic loss at a specific chromosomal region denotes the presence of a candidate tumor-suppressor gene, including APC on chromosome 5q, TP53 on chromosome 17p, DCC netrin 1 receptor (DCC), SMAD family member (SMAD2 and SMAD4) on chromosome 18q (31). In contrast, a gain of chromosomal material suggests the presence of the potential oncogenes or genes that favor cell growth or survival. In CRC, gains at chromosome 7, and chromosomal arms 1q, 8q, 12q, 13q and 20q have been repeatedly reported by different research groups (2631). It was reasoned that these chromosomal changes are associated with a gain and loss of function of tumor-associated genes offering mutated cells growth and survival advantages, leading to progressive conversion of normal cells into cancer cells (32,33). However, the gains/losses of chromosomal materials generally span a large region and comprise a large number of genes making identification of target genes challenging.

In the field of stem cell research, genetic analysis of human embryonic stem cell (hESC) lines, a pluripotent cell type that shares numerous characteristics with cancer cells, has also revealed multiple CNVs, and few of them are also recurrent, including losses of chromosomal band 18q21qter, and whole or partial gains of chromosomes 1, 12, 17 and 20 (34,35). Notably, 20q11.21 amplification was identified in >20% of the screened hESC lines (36). Previously, BCL2 like 1 (BCL2L1), which is located in the smallest common chromosomal region of gain and regulates the mitochondrial apoptotic pathway, has been confirmed as the key-driver gene of this amplification (37,38). Accordingly, the overexpression of Bcl-xL, an anti-apoptotic isoform of BCL2L1 has offered cells a survival advantage by preventing apoptosis (37,38). Overexpression of this gene may also be responsible for the gain of 20q in various human cancer types (39).

Losses of 18q

Allelic loss at chromosome 18q is detected in ~70% of primary CRC in the late carcinogenic process (29,31,40,41), and is considered as a poor prognosis marker for survival in patients with CRC (42,43). The high frequency of allelic deletions involving chromosome 18q suggests the presence of candidate tumor-suppressor genes whose inactivation may serve a significant role in CRC, including DCC, SMAD2 and SMAD4 (12,25,44). DCC, located in the chromosome band 18q21.2, encoding a component of the neutrin-1 receptor, was proposed as a putative tumor-suppressor gene (45). However, much of the reported data on the loss and inactivation of DCC is circumstantial and fails to provide conclusive evidence that DCC functions as a tumor-suppressor gene (46). Furthermore, to the best of our knowledge, there is no evidence that germline mutations of DCC serve a role in heritable cancer; and few somatic mutations in DCC have been reported in CRC (46). The presence of two other well-established tumor suppressor genes, SMAD2 and SMAD4 in the region of loss also challenges the function of DCC as a tumor-suppressor gene (47,48). In fact, SMAD2 and SMAD4 genes are localized in 18q21.1, the common region of loss of 18q in CRC (25). These SMAD genes encode downstream signal transducers for transforming growth factor-β (TGF-β), and their alterations may confer resistance to TGF-β and contribute to tumorigenesis (49). SMAD4 was identified to be inactivated in ~60% of pancreatic cancer (50). However, the frequency of SMAD4 and SMAD2 somatic mutations is relatively low in CRC (5153). Nevertheless, smaller regions of loss, which exclude SMAD2 and SMAD4, have been reported in head and neck squamous cancer (54). In addition, their gene expression is retained in CRC with LOH of 18q (46). Taken together, these observations suggest that SMAD2 and SMAD4 are unlikely to constitute the major chromosome 18q target for inactivation in CRC, and that other tumor suppressor genes besides the DCC and SMAD genes may be the target for chromosome 18q loss.

APC/β-catenin

Activation of the Wnt signaling pathway via mutation of the APC, a multi-functional tumor-suppressor gene on 5q22.2, is essential and the earliest event in the development of CRC (55). APC protein is a key component of the β-catenin destruction complex involved in the degradation and suppression of the Wnt/β-catenin signaling pathway (56). Mutant APC disrupts the formation of the destruction complex leading to stabilization and accumulation of β-catenin protein in the cytoplasm. Accumulated β-catenin protein is translocated to the cell nucleus where it forms complexes with TCF/LEF, and induces overactivation of Wnt downstream effectors that, in turn, promote the proliferation, migration, invasion and metastasis of cancerous cells (57). The same outcome is also observed with mutations in β-catenin (58) and AXIN2 (57), but to a lesser extent. Notably, mutations in AXIN2 have been reported in CRC with MSI only (59).

APC mutations or allelic losses have been identified in ~90% of patients with CRC (60). Germline mutations in APC are responsible for FAP (15), while somatic mutations and/or allelic deletions of APC are described in sporadic CRC (61). The APC gene may also be epigenetically inactivated through promoter hypermethylation that has been identified in 18% of primary colorectal carcinoma and adenoma cases (62).

TP53

TP53 is a tumor-suppressor gene located on the short arm of chromosome 17, which is commonly lost in colorectal carcinoma (40). TP53 has been defined as the ‘guardian of the genome’ because it encodes a transcription factor that regulates the transcription of hundreds of genes involved in different processes, including DNA repair, cell cycle arrest, senescence, apoptosis and metabolism in response to a variety of the stress signals (63). Upon DNA damage, for example, TP53 induces cell cycle arrest at the G1 or G2 phase, or triggers apoptosis when the damage is too severe and irreparable (64). Loss of TP53 function, therefore, contributes to the propagation of damaged DNA to daughter cells.

TP53 alteration is the hallmark of human tumors, and the status of TP53 mutation is associated with the progression and outcome of sporadic CRC (65). Particularly, TP53 loss of function has been reported in 50–75% of CRC cases, much higher compared with that in adenoma, indicating its role in the transition from an adenoma to carcinoma (66,67). To date, the majority of the TP53 mutations reported in CRC are missense mutations that substitute AT for GC (68). Liu and Bodmer (69) have analyzed TP53 mutations and their expression in 56 CRC cell lines, and reported a relatively high frequency of TP53 mutations (76.8%), in which missense mutations accounted for 47.83% and point mutations that are transitions at CpG sites accounted for 37.5%. These mutations render an inactive protein with an abnormally long half-life that is detectable by immunohistochemistry (70).

KRAS

The KRAS gene belongs to the RAS gene family involved in signaling pathways that regulate cellular proliferation, differentiation or survival. KRAS is a membrane-bound GTP/GDP-binding protein with intrinsic GTPase activity and is expressed in the majority of human cells. The switch between its active GTP-bound state and the inactive GDP-bound state is regulated by GTPase-activating proteins and guanine nucleotide exchange factors (71). The KRAS mutations impair the intrinsic GTPase activity of KRAS, causing the accumulation of the KRAS proteins at the GTP-bound active state, eventually resulting in the constitutive activation of the downstream proliferative signaling pathways (72).

Oncogenic mutations in the RAS gene have been identified in ~30% of all human tumors (73), in which mutations in KRAS accounted for ~85%, NRAS proto-oncogene GTPase (NRAS) for ~15%, and HRas proto-oncogene GTPase (HRAS) for <1% (7476). The high frequency of KRAS mutations and its appearance at a relatively early stage in tumor progression suggest a causative role of KRAS in human tumorigenesis. Several studies have reported an association between KRAS mutations, and poor prognosis of CRC (77,78), and lung (79,80) and liver (81) metastasis. In contrast, several other studies reported that KRAS mutations were strong independent predictors of survival in patients with CRC (8082). These contradictory findings may be explained by the differences in the distribution of specific KRAS mutations, stage at diagnosis or other characteristics. KRAS mutations have emerged as an important predictive marker of resistance to anti-epidermal growth factor receptors (EGFR) agents, including panitumumab and cetuximab (8386).

Activating KRAS mutations have been identified in 35–45% of CRC cases (40,80,8789), and primarily occur in codon 12 and 13 (75,89). The most frequent changes observed in these codons are the substitution of glycine for aspartate (p.G12D, p.G13D) (90). The mutation rates of NRAS, in contrast, are lower (1–3%) and activating mutations of HRAS has not been detected in CRC (40,91,92). Previously, pyrosequencing of KRAS, BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α revealed that 53.8% of patients exhibit a KRAS mutation in codons 12 or 13, of which 57.9% were c.38G>A (pG13D), and 22.2% were c35G>T (p.G12V) mutations (93).

MSI

Another type of genomic instability is MSI, a typical characteristic of cancerous cells, occurring in 15–20% of sporadic CRC and in >95% of HNPPC. Microsatellites are repetitive DNA sequences consisting of tandem repeats, usually between one to five base pairs. Patients with MSI phenotype exhibit a high frequency of replication errors, particularly in repetitive DNA sequences, primarily due to the slippage of the DNA polymerase (94). The progressive insertion/deletions of nucleotides within the microsatellite sequences result in the appearance of longer or shorter alleles compared with those detected in the normal cells of the same individual (95,96).

To access the MSI status of a cancer, a standard panel of five microsatellite markers, including two mononucleotide (BAT26 and BAT25) and three dinucleotide (D2S123, D5S346, and D17S250) repeats, has been recommended according to the Bethesda Guidelines (97). Tumors are then classified based on the number of microsatellites exhibiting instability. Particularly, tumors are classified as MSI high (MSI-H) when ≥30% of the markers exhibit instability; those with <30% markers exhibiting instability are defined as MSI low, and those with no apparent instability are microsatellite stable (MSS) (97,98).

It is now accepted that MSI is associated with post-replicative DNA MMR deficiency, primarily involving mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) (94,99101). Impairment of MMR genes can occur by either mutational inactivation or by epigenetic inactivation through CpG island methylation of the promoter of the genes. Loss or insufficiency of MMR activity leads to replication errors with an increased mutation rate and a higher potential for malignancy. In MSI-H gastric cancer, for example, hypermethylation of MLH1 promoter is responsible for the development of >50% of cases, whereas mutations in MLH1 and MSH2 account for ~15% of cases (102,103).

Small insertions/deletions may create frame-shift mutations within repetitive tracts present in the coding region of essential tumor-suppressor or tumor-associated genes, resulting in an inactive protein and contributing to tumorigenesis in cancers with MSI-H (104). Using a large-scale genomic screen of coding region microsatellites, Mori et al (105) identified nine loci that were mutated in >20% of tumors, namely: Transforming growth factor-β receptor (TGFBR2) (79.1%), BCL2 associated X apoptosis regulator (BAX) (37.5%), human mutS homolog 3 (26.2%), activin A receptor, type II (58.1%), SEC63 homolog protein translocation regulator (48.8%), absent in melanoma 2 (47.6%), NADH-ubiquinone oxidoreductase (27.9%), cordon-bleu WH2 repeat protein like 1 (23.8%) and proliferation-associated 2G4/ErbB3-binding protein 1 (20.9%). TGFBR2, encoding a kinase receptor involved in transduction of the TGFB1/2/3 signal from the cell surface to the cytoplasm to inhibit cellular proliferation, is the most commonly affected gene. Particularly, instability in the poly-adenine tract of this gene has been detected in ~85% of MSI-H colorectal tumors, rendering an inactive receptor and thus eliminating the growth-suppressive effects of TGFB1 (106). Another commonly mutated gene in CRC is BAX, a pro-apoptotic gene belonging to the BCL2 family. Frame-shift mutations within the poly-guanine sequence have been detected in 50% of MSI-H colorectal tumors, causing silencing of this gene and suppressing apoptosis (107). These alterations in the gene functions represent a possible mechanism for MSI carcinogenesis.

CIMP or aberrant DNA methylation

Transcription inactivation by DNA hypermethylation at promoter CpG islands of tumor-suppressor genes, causing gene silencing, is now recognized as an important mechanism in human carcinogenesis (108111). The CpG island methylator phenotype has been identified in 30–35% colorectal adenoma cases, and is considered as an early event and a characteristic for the serrated pathway of colorectal tumorigenesis (108,112,113). However, the quantitative DNA methylation study performed by Ogino et al (114) reported that CIMP accounts for 17% of CRC, which is less frequent compared with previously reported and that clinical features of CIMP are similar to those of MSI-associated CRC (114). Notably, sporadic MSI colorectal tumors are almost exclusively associated with CIMP-associated methylation of MLH1 leading to inactivation of this gene (107,115). In contrast, the familial MSI cases (Lynch syndrome) are generally caused by germline mutations in the MMR genes, primarily including MLH1 and MSH2, and accounts for <5% of all CRC cases (Fig. 2) (107,116).

The CIMP status of CRC is currently assessed by a panel of methylation markers categorizing CRC as exhibiting or not exhibiting DNA methylation on the basis of certain thresholds (114,115,117,118). CIMP+ colorectal tumors appear to have a distinct profile, including associations with the proximal colon, poor differentiation, MSI status, BRAF mutation and wild-type KRAS (113115,119121). Particularly, the frequency of BRAF mutations in CIMP+ tumors is significantly higher compared with their CIMP counterparts (114,115). Shen et al (122) analyzed the genetic and epigenetic alterations in 97 primary CRC samples, and demonstrated that CIMP-high tumors are associated with MSI status (80%) and BRAF mutation (53%); CIMP-low tumors are associated with KRAS mutations (92%); and CIMP tumors typically have a high rate of p53 mutations (71%) (122). Furthermore, CIMP status has also been indicated to be negatively associated with 18q LOH status in colorectal tumors (117). Particularly, CIMP-0 was associated with 18q LOH-positive tumors and vice versa (117).

Clinical implication of the molecular genetics of CRC

The prognosis and therapeutic options for patients with CRC are associated with the stage at which they are first diagnosed. While early stage CRC is often cured with surgery alone, more advanced or metastatic CRC generally require additional adjuvant chemotherapy or targeted therapy, either alone or as a combined treatment. Early detection of CRC thus becomes important to reduce the incidence and mortality of the disease. Furthermore, due to their heterogeneity, the benefits from adjuvant chemotherapy for stage II and III CRC patients may vary largely. Thus, identifying molecular prognostic markers that are capable of recognizing patients with CRC more likely to recur or benefit from adjuvant chemotherapy may improve the prognosis and assist in the selection of appropriate therapy, and subsequently the general outcomes.

It is now widely known that certain alterations at the molecular level favor CRC onset, progression and metastasis (60). Several known mutations are considered to be associated with a poorer patient outcome and/or failure of response to a certain therapy (18). Patients with inactive TP53 mutations, for example, are at an increased risk of mortality compared with their counterparts, but this mutation does not appear to affect the outcome of chemotherapy (123). However, the presence of somatic KRAS mutations has been considered as a predictor of resistance to anti-EGFR therapy (8386,124). Thus, KRAS mutation status is currently used in clinical settings to predict the therapeutic effectiveness of CRC prior to chemotherapy to avoid any undesired effects and medical costs (125). APC is another commonly affected gene whose mutations generally appear in the early stage of CRC development (55,60). Notably, the risk of CRC for a patient with FAP, which begins with a germline mutation in one allele of the APC gene is ~100% by the age of 40 years (6,7). Therefore, APC mutations are being considered as good diagnostic markers for identifying individuals at risk of CRC.

The majority (~75%) of CRC with MSI are sporadic cases caused by the loss of DNA MMR activity due to methylation of the promoter of the MLH1 gene, while the other 25% of cases are classified as Lynch syndrome caused by germline mutations in the MMR genes (Fig. 2). Generally, MSI is detected earlier in life in patients with Lynch syndrome (<50 years old) as compared with the sporadic cases (>65 years old) (126). Particularly, CRC with MSI are more likely to occur in the proximal colon (126). Evidence has suggested that MSI is a favorable prognostic biomarker for CRC (127129). However, its predictive role for the response to chemotherapeutic agents, including 5-fluorouracil (5-FU) is conflicting. Several studies demonstrated a lack of benefit of 5-FU-based adjuvant chemotherapy in patients with CRC with MSI tumors (130133), while others reported the beneficial effects (127,134). Des Guetz et al (135) performed a meta-analysis involving 3,690 patients from seven different studies, and reported that chemotherapy had a beneficial effect among MSS, but not MSI-H patients (135). In addition, the more improved survival rate of MSI-H patients was due to a better prognosis rather than the benefit of chemotherapy (135). These findings suggested that MSI may be considered as a predictive marker of chemoresistance and that patients with CRC with MSI may be spared from adjuvant treatment. The MSI status among patients with CRC, thus, is highly valuable in prognosis and therapy of CRC, and should be thoroughly evaluated by performing polymerase chain reaction analysis using the Bethesda panel and/or immunohistochemistry staining for DNA MMR proteins, including MLH1 and MSH2, in order to contribute to treatment decision-making regarding chemotherapy administration.

Several groups have used gene expression profiling to classify CRC, and to identify genes associated with prognosis and prediction of disease outcome. De Sousa et al (136) used an unsupervised classification strategy involving >1,100 individuals with colon cancer and defined three main colon cancer subtypes. Two subtypes are associated with two well-characterized subsets of colon cancer, namely the CIN and the MSI group. The third subtype was largely MSS and overlaps partly with the CIMP group, and is associated with poor prognosis and resistance to anti-EGFR therapy (136). Using a similar approach, Sadanandam et al (137) defined six clinically relevant CRC subtypes by associating their gene expression profiles with corresponding clinical response to cetuximab. Patients with stem-like subtype and inflammatory subtype tumors, with poor and intermediate disease-free survival, exhibited an improved response to the combination chemotherapy regimen FOLFIRI (5-FU with irinotecan) in adjuvant or metastatic settings, whereas transit-amplifying- and goblet-like-subtype tumors, with markedly better prognosis, did not appear to benefit from these treatments. However, cetuximab-sensitive transit-amplifying and cetuximab-resistant transit-amplifying subtypes may be efficiently treated with cetuximab or a cMET inhibitor, respectively, in the metastatic setting (137). Although there are significant associations between MSI status and specific subtypes, the transcriptional signatures-based subtypes allow better refinement and provide insights for the development of subtype-specific therapies, which, in turn, may contribute to the more effective management of this disease.

Conclusion and future perspectives

Despite the great advancement in CRC research, the role of the molecular characterization in diagnostic tests and therapeutic decisions remains limited due to the fact that the function of the majority of mutations remains unclear and rarely provides any valuable diagnostic information. Further research is required to develop more easily applicable molecular tests for early detection of CRC, which is essential to improving the prognosis and treatment efficiency. Furthermore, it is essential to identify novel therapeutic targets as the majority of CRC cases are insensitive to EGFR inhibitor therapy.

Recent studies have provided a better understanding of CRC and assist in the development of novel treatment regimens. Particularly, the implementation of targeted next-generation sequencing (NGS) in clinical settings allows a reliable identification of the most common mutations, and is able to guide therapeutic decisions for patients with CRC based on personalized medicine (138). NGS is currently the most important technology for early diagnosis and prognosis, as well as identification of novel predictive biomarkers for available treatments with targeted therapy and immunotherapy for patients with CRC (138). Specifically, the combination of CRISPR/Cas9 technology and immunotherapy would significantly improve patient care by reducing side effects (139,140).

Acknowledgements

The authors would like to thank Dr. Adam F. Johnson (Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Danang, Vietnam) for the critical reading of the manuscript.

Funding

This study was supported by the National Foundation for Science and Technology Development (NAFOSTED; grant no. 106-YS.01-2015.12).

Availability of data and materials

Not applicable.

Authors' contributions

HTN conceptualized the article, critically discussed the findings and co-wrote the article. HQD co-wrote the article. Both authors revised the article and approved the final version.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Burt R: Inheritance of colorectal cancer. Drug Discov Today Dis Mech. 4:293–300. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Hendon SE and DiPalma JA: U.S. practices for colon cancer screening. Keio J Med. 54:179–183. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Lengauer C, Kinzler KW and Vogelstein B: Genetic instabilities in human cancers. Nature. 396:643–649. 1998. View Article : Google Scholar : PubMed/NCBI

6 

Markowitz SD and Bertagnolli MM: Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 361:2449–2460. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Tsang AH, Cheng KH, Wong AS, Ng SS, Ma BB, Chan CM, Tsui NB, Chan LW, Yung BY and Wong SC: Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 20:3847–3857. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Grady WM and Pritchard CC: Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 42:124–139. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Fransén K, Klintenäs M, Österström A, Dimberg J, Monstein HJ and Söderkvist P: Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 25:527–533. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Pino MS and Chung DC: The chromosomal instability pathway in colon cancer. Gastroenterology. 138:2059–2072. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Lynch HT and de la Chapelle A: Hereditary colorectal cancer. N Engl J Med. 348:919–932. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI

13 

Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI

14 

Grady WM: Epigenetic events in the colorectum and in colon cancer. Biochem Soc Trans. 33:684–688. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Kinzler KW and Vogelstein B: Lessons from hereditary colorectal cancer. Cell. 87:159–170. 1996. View Article : Google Scholar : PubMed/NCBI

16 

Tejpar S and Van Cutsem E: Molecular and genetic defects in colorectal tumorigenesis. Best Pract Res Clin Gastroenterol. 16:171–185. 2002. View Article : Google Scholar : PubMed/NCBI

17 

O'Connell JB, Maggard MA and Ko CY: Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 96:1420–1425. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Reimers MS, Zeestraten EC, Kuppen PJ, Liefers GJ and van de Velde CJ: Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf). 1:166–183. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Nachman MW and Crowell SL: Estimate of the mutation rate per nucleotide in humans. Genetics. 156:297–304. 2000.PubMed/NCBI

20 

Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, et al: Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 328:636–639. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Loeb LA, Loeb KR and Anderson JP: Multiple mutations and cancer. Proc Natl Acad Sci USA. 100:776–781. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, et al: Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 268:1336–1338. 1995. View Article : Google Scholar : PubMed/NCBI

23 

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riqqins GJ, et al: High frequency of mutations of the PIK3CA gene in human cancers. Science. 304:5542004. View Article : Google Scholar : PubMed/NCBI

24 

Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, et al: Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 244:217–221. 1989. View Article : Google Scholar : PubMed/NCBI

25 

Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, Willson JK, Markowitz S, Hamilton SR, Kern SE, et al: Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 13:343–346. 1996. View Article : Google Scholar : PubMed/NCBI

26 

Diep CB, Kleivi K, Ribeiro FR, Teixeira MR, Lindgjærde OC and Lothe RA: The order of genetic events associated with colorectal cancer progression inferred from meta-analysis of copy number changes. Genes Chromosomes Cancer. 45:31–41. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Jasmine F, Rahaman R, Dodsworth C, Roy S, Paul R, Raza M, Paul-Brutus R, Kamal M, Ahsan H and Kibriya MG: A genome-wide study of cytogenetic changes in colorectal cancer using SNP microarrays: Opportunities for future personalized treatment. PLoS One. 7:e319682012. View Article : Google Scholar : PubMed/NCBI

28 

Baudis M: Genomic imbalances in 5918 malignant epithelial tumors: An explorative meta-analysis of chromosomal CGH data. BMC Cancer. 7:2262007. View Article : Google Scholar : PubMed/NCBI

29 

Jones AM, Douglas EJ, Halford SE, Fiegler H, Gorman PA, Roylance RR, Carter NP and Tomlinson IP: Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma. Oncogene. 24:118–129. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Zarzour P, Boelen L, Luciani F, Beck D, Sakthianandeswaren A, Mouradov D, Sieber OM, Hawkins NJ, Hesson LB, Ward RL and Wong JW: Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas. Genes Chromosomes Cancer. 54:303–314. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Foulds L: The natural history of cancer. J Chronic Dis. 8:2–37. 1958. View Article : Google Scholar : PubMed/NCBI

33 

Nowell PC: The clonal evolution of tumor cell populations. Science. 194:23–28. 1976. View Article : Google Scholar : PubMed/NCBI

34 

Nguyen HT, Geens M and Spits C: Genetic and epigenetic instability in human pluripotent stem cells. Hum Reprod Update. 19:187–205. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Lund RJ, Närvä E and Lahesmaa R: Genetic and epigenetic stability of human pluripotent stem cells. Nat Rev Genet. 13:732–744. 2012. View Article : Google Scholar : PubMed/NCBI

36 

International Stem Cell Initiative, . Amps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H, Baker J, Barker D, Munoz MB, et al: Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol. 29:1132–1144. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Nguyen HT, Geens M, Mertzanidou A, Jacobs K, Heirman C, Breckpot K and Spits C: Gain of 20q11.21 in human embryonic stem cells improves cell survival by increased expression of Bcl-xL. Mol Hum Reprod. 20:168–177. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Avery S, Hirst AJ, Baker D, Lim CY, Alagaratnam S, Skotheim RI, Lothe RA, Pera MF, Colman A, Robson P, et al: BCL-XL Mediates the strong selective advantage of a 20q11.21 amplification commonly found in human embryonic stem cell cultures. Stem Cell Reports. 1:379–386. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al: The landscape of somatic copy-number alteration across human cancers. Nature. 463:899–905. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL: Genetic alterations during colorectal-tumor development. N Engl J Med. 319:525–532. 1988. View Article : Google Scholar : PubMed/NCBI

41 

Ogino S, Nosho K, Irahara N, Shima K, Baba Y, Kirkner GJ, Meyerhardt JA and Fuchs CS: Prognostic significance and molecular associations of 18q loss of heterozygosity: A cohort study of microsatellite stable colorectal cancers. J Clin Oncol. 27:4591–4598. 2009. View Article : Google Scholar : PubMed/NCBI

42 

Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F, Paty PB, Gerald WL, Notterman DA and Domany E: Association of survival and disease progression with chromosomal instability: A genomic exploration of colorectal cancer. Proc Natl Acad Sci USA. 106:7131–7136. 2009. View Article : Google Scholar : PubMed/NCBI

43 

Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B and Hamilton SR: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 331:213–221. 1994. View Article : Google Scholar : PubMed/NCBI

44 

Zauber P, Sabbath-solitare M, Marotta SP and Bishop T: Loss of heterozygosity for chromosome 18q and microsatellite instability are highly consistent across the region of the DCC and SMAD4 genes in colorectal carcinomas and adenomas. J Appl Res. 8:14–23. 2008.

45 

Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, et al: Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 247:49–56. 1990. View Article : Google Scholar : PubMed/NCBI

46 

Mehlen P and Fearon ER: Role of the dependence receptor DCC in colorectal cancer pathogenesis. J Clin Oncol. 22:3420–3428. 2004. View Article : Google Scholar : PubMed/NCBI

47 

Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Järvinen H, Mecklin JP, Hemminki A, Schwartz S Jr, Aaltonen LA and Arango D: SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res. 11:2606–2611. 2005. View Article : Google Scholar : PubMed/NCBI

48 

Grady WM: Genomic instability and colon cancer. Cancer Metastasis Rev. 23:11–27. 2004. View Article : Google Scholar : PubMed/NCBI

49 

Shi Y, Hata A, Lo RS, Massagué J and Pavletich NP: A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 388:87–93. 1997. View Article : Google Scholar : PubMed/NCBI

50 

Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hurban RH and Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 271:350–353. 1996. View Article : Google Scholar : PubMed/NCBI

51 

Takagi Y, Kohmura H, Futamura M, Kida H, Tanemura H, Shimokawa K and Saji S: Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 111:1369–1372. 1996. View Article : Google Scholar : PubMed/NCBI

52 

Takagi Y, Koumura H, Futamura M, Aoki S, Ymaguchi K, Kida H, Tanemura H, Shimokawa K and Saji S: Somatic alterations of the SMAD-2 gene in human colorectal cancers. Br J Cancer. 78:1152–1155. 1998. View Article : Google Scholar : PubMed/NCBI

53 

Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M, Day F, Li S, Tsui C, Lipton L, et al: SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 73:725–735. 2013. View Article : Google Scholar : PubMed/NCBI

54 

Takebayashi S, Ogawa T, Jung KY, Muallem A, Mineta H, Fisher SG, Grenman R and Carey TE: Identification of new minimally lost regions on 18q in head and neck squamous cell carcinoma. Cancer Res. 60:3397–3403. 2000.PubMed/NCBI

55 

Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B and Kinzler KW: APC mutations occur early during colorectal tumorigenesis. Nature. 359:235–237. 1992. View Article : Google Scholar : PubMed/NCBI

56 

MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI

57 

Stanczak A, Stec R, Bodnar L, Olszewski W, Cichowicz M, Kozlowski W, Szcylik C, Pietrucha T, Wieczorek M and Lamparska-Pzybysz M: Prognostic significance of Wnt-1, β-catenin and E-cadherin expression in advanced colorectal carcinoma. Pathol Oncol Res. 17:955–963. 2011. View Article : Google Scholar : PubMed/NCBI

58 

Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW: Activation of β-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 275:1787–1790. 1997. View Article : Google Scholar : PubMed/NCBI

59 

Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, et al: Mutations in AXIN2 cause colorectal cancer with defective mismatch repair. Nat Genet. 26:146–147. 2000. View Article : Google Scholar : PubMed/NCBI

60 

Coppedè F, Lopomo A, Spisni R and Migliore L: Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 20:943–956. 2014. View Article : Google Scholar : PubMed/NCBI

61 

Kapitanović S, Cacev T, Radosević S, Spaventi S, Spaventi R and Pavelić K: APC gene loss of heterozygosity, mutations, E1317Q, and I1307K germ-line variants in sporadic colon cancer in Croatia. Exp Mol Pathol. 77:193–200. 2004. View Article : Google Scholar : PubMed/NCBI

62 

Esteller M: Epigenetic lesions causing genetic lesions in human cancer: Promoter hypermethylation of DNA repair genes. Eur J Cancer. 36:2294–2300. 2000. View Article : Google Scholar : PubMed/NCBI

63 

Levine AJ: P53, the cellular gatekeeper for growth and division. Cell. 88:323–331. 1997. View Article : Google Scholar : PubMed/NCBI

64 

el-Deiry WS: Regulation of p53 downstream genes. Semin Cancer Biol. 8:345–357. 1998. View Article : Google Scholar : PubMed/NCBI

65 

Li XL, Zhou J, Chen ZR and Chng WJ: P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 21:84–93. 2015. View Article : Google Scholar : PubMed/NCBI

66 

Leslie A, Carey FA, Pratt NR and Steele RJ: The colorectal adenoma-carcinoma sequence. Br J Surg. 89:845–860. 2002. View Article : Google Scholar : PubMed/NCBI

67 

Takayama T, Miyanishi K, Hayashi T, Sato Y and Niitsu Y: Colorectal cancer: Genetics of development and metastasis. J Gastroenterol. 41:185–192. 2006. View Article : Google Scholar : PubMed/NCBI

68 

Sigal A and Rotter V: Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome. Cancer Res. 60:6788–6793. 2000.PubMed/NCBI

69 

Liu Y and Bodmer WF: Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. Proc Natl Acad Sci USA. 103:976–981. 2006. View Article : Google Scholar : PubMed/NCBI

70 

Béroud C and Soussi T: The UMD-p53 database: New mutations and analysis tools. Hum Mutat. 21:176–181. 2003. View Article : Google Scholar : PubMed/NCBI

71 

Vigil D, Cherfils J, Rossman KL and Der CJ: Ras superfamily GEFs and GAPs: Validated and tractable targets for cancer therapy? Nat Rev Cancer. 10:842–857. 2010. View Article : Google Scholar : PubMed/NCBI

72 

Schubbert S, Shannon K and Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 7:295–308. 2007. View Article : Google Scholar : PubMed/NCBI

73 

Adjei AA: Ras signaling pathway proteins as therapeutic targets. Curr Pharm Des. 7:1581–1594. 2001. View Article : Google Scholar : PubMed/NCBI

74 

Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 3:11–22. 2003. View Article : Google Scholar : PubMed/NCBI

75 

Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, et al: COSMIC: Mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res. 39:(Database issue). D945–D950. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Tan C and Du X: KRAS mutation testing in metastatic colorectal cancer. World J Gastroenterol. 18:5171–5180. 2012.PubMed/NCBI

77 

Conlin A, Smith G, Carey FA, Wolf CR and Steele RJ: The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma. Gut. 54:1283–1286. 2005. View Article : Google Scholar : PubMed/NCBI

78 

Phipps AI, Buchanan DD, Makar KW, Win AK, Baron JA, Lindor NM, Potter JD and Newcomb PA: KRAS-mutation status in relation to colorectal cancer survival: The joint impact of correlated tumour markers. Br J Cancer. 108:1757–1764. 2013. View Article : Google Scholar : PubMed/NCBI

79 

Cejas P, López-Gómez M, Aguayo C, Madero R, de Castro Carpeño J, Belda-Iniesta C, Barriuso J, García Moreno V, Larrauri J, López R, et al: KRAS mutations in primary colorectal cancer tumors and related metastases: A potential role in prediction of lung metastasis. PLoS One. 4:e81992009. View Article : Google Scholar : PubMed/NCBI

80 

Kim HS, Heo JS, Lee J, Lee JY, Lee MY, Lim SH, Lee WY, Kim SH, Park YA, Cho YB, et al: The impact of KRAS mutations on prognosis in surgically resected colorectal cancer patients with liver and lung metastases: A retrospective analysis. BMC Cancer. 16:1202016. View Article : Google Scholar : PubMed/NCBI

81 

Nash GM, Gimbel M, Shia J, Nathanson DR, Ndubuisi MI, Zeng ZS, Kemeny N and Paty PB: KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 17:572–578. 2010. View Article : Google Scholar : PubMed/NCBI

82 

Inoue Y, Saigusa S, Iwata T, Okugawa Y, Toiyama Y, Tanaka K, Uchida K, Mohri Y and Kusunoki M: The prognostic value of KRAS mutations in patients with colorectal cancer. Oncol Rep. 28:1579–1584. 2012. View Article : Google Scholar : PubMed/NCBI

83 

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suqqs S, Radinsky R, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 26:1626–1634. 2008. View Article : Google Scholar : PubMed/NCBI

84 

Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 26:374–379. 2008. View Article : Google Scholar : PubMed/NCBI

85 

Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitalle S, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 359:1757–1765. 2008. View Article : Google Scholar : PubMed/NCBI

86 

Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J and Bardelli A: Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 101:1308–1324. 2009. View Article : Google Scholar : PubMed/NCBI

87 

Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ and Vogelstein B: Prevalence of ras gene mutations in human colorectal cancers. Nature. 327:293–297. 1987. View Article : Google Scholar : PubMed/NCBI

88 

Forrester K, Almoguera C, Han K, Grizzle WE and Perucho M: Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 327:298–303. 1987. View Article : Google Scholar : PubMed/NCBI

89 

Fernández-Medarde A and Santos E: Ras in cancer and developmental diseases. Genes Cancer. 2:344–358. 2011. View Article : Google Scholar : PubMed/NCBI

90 

Neumann J, Zeindl-Eberhart E, Kirchner T and Jung A: Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 205:858–862. 2009. View Article : Google Scholar : PubMed/NCBI

91 

Irahara N, Baba Y, Nosho K, Shima K, Yan L, Dias-Santagata D, Iafrate AJ, Fuchs CS, Haigis KM and Ogino S: NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. 19:157–163. 2010. View Article : Google Scholar : PubMed/NCBI

92 

Vaughn CP, ZoBell SD, Furtado LV, Baker CL and Samowitz WS: Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 50:307–312. 2011. View Article : Google Scholar : PubMed/NCBI

93 

Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, Mourtzoukou D, Kontogeorgos G, Zografos G and Pintzas A: Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat. 35:329–340. 2014. View Article : Google Scholar : PubMed/NCBI

94 

Abdel-Rahman WM and Peltomäki P: Molecular basis and diagnostics of hereditary colorectal cancers. Ann Med. 36:379–388. 2014. View Article : Google Scholar

95 

Thibodeau SN, Bren G and Schaid D: Microsatellite instability in cancer of the proximal colon. Science. 260:816–819. 1993. View Article : Google Scholar : PubMed/NCBI

96 

Boland CR and Goel A: Somatic evolution of cancer cells. Semin Cancer Biol. 15:436–450. 2005. View Article : Google Scholar : PubMed/NCBI

97 

Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava S: A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58:5248–5257. 1998.PubMed/NCBI

98 

Findeisen P, Kloor M, Merx S, Sutter C, Woerner SM, Dostmann N, Benner A, Dondog B, Pawlita M, Dippold W, et al: T25 repeat in the 3′ untranslated region of the CASP2 gene: A sensitive and specific marker for microsatellite instability in colorectal cancer. Cancer Res. 65:8072–8078. 2005. View Article : Google Scholar : PubMed/NCBI

99 

Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR, et al: Clues to the pathogenesis of familial colorectal cancer. Science. 260:812–816. 1993. View Article : Google Scholar : PubMed/NCBI

100 

Jiricny J: The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 7:335–346. 2006. View Article : Google Scholar : PubMed/NCBI

101 

Pal T, Permuth-Wey J and Sellers TA: A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer. 113:733–742. 2008. View Article : Google Scholar : PubMed/NCBI

102 

Grady WM and Carethers JM: Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 135:1079–1099. 2008. View Article : Google Scholar : PubMed/NCBI

103 

Hudler P: Genetic aspects of gastric cancer instability. Scientific World Journal. 2012:7619092012. View Article : Google Scholar : PubMed/NCBI

104 

Perucho M: Cancer of the microsatellite mutator phenotype. Biol Chem. 377:675–684. 1996.PubMed/NCBI

105 

Mori Y, Yin J, Rashid A, Leggett BA, Young J, Simms L, Kuehl PM, Langenberg P, Meltzer SJ and Stine OC: Instabilotyping: Comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res. 61:6046–6049. 2001.PubMed/NCBI

106 

Parsons R, Myeroff LL, Liu B, Wilison JK V, Markowitz SD, Kinzler KW and Vogelstein B: Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Res. 55:5548–5550. 1995.PubMed/NCBI

107 

Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology. 138:2073–2087.e3. 2010. View Article : Google Scholar : PubMed/NCBI

108 

Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB and Issa JP: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 96:8681–8686. 1999. View Article : Google Scholar : PubMed/NCBI

109 

Lao VV and Grady WM: Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 8:686–700. 2011. View Article : Google Scholar : PubMed/NCBI

110 

Jones PA and Laird PW: Cancer epigenetics comes of age. Nat Genet. 21:163–167. 1999. View Article : Google Scholar : PubMed/NCBI

111 

Laird PW: Cancer epigenetics. Hum Mol Genet. 14:R65–R76. 2005. View Article : Google Scholar : PubMed/NCBI

112 

Jass JR: Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol. 2:398–405. 2005. View Article : Google Scholar : PubMed/NCBI

113 

Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, Wolff RK and Slattery ML: Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 129:837–845. 2005. View Article : Google Scholar : PubMed/NCBI

114 

Ogino S, Cantor M, Kawasaki T, Brahmandam M, Kirkner GJ, Weisenberger DJ, Campan M, Laird PW, Loda M and Fuchs CS: CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut. 55:1000–1006. 2006. View Article : Google Scholar : PubMed/NCBI

115 

Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, et al: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 38:787–793. 2006. View Article : Google Scholar : PubMed/NCBI

116 

Worthley DL and Leggett BA: Colorectal cancer: Molecular features and clinical opportunities. Clin Biochem Rev. 31:31–38. 2010.PubMed/NCBI

117 

Ogino S, Kawasaki T, Kirkner GJ, Ohnishi M and Fuchs CS: 18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high. BMC Cancer. 7:722007. View Article : Google Scholar : PubMed/NCBI

118 

Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M and Fuchs CS: Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn. 9:305–314. 2007. View Article : Google Scholar : PubMed/NCBI

119 

Toyota M, Ohe-Toyota M, Ahuja N and Issa JP: Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA. 97:710–715. 2000. View Article : Google Scholar : PubMed/NCBI

120 

Kambara T, Simms LA, Whitehall VLJ, Spring KJ, Wynter CVA, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, et al: BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 53:1137–1144. 2004. View Article : Google Scholar : PubMed/NCBI

121 

Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, OConnor T and Ward R: CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology. 122:1376–1387. 2002. View Article : Google Scholar : PubMed/NCBI

122 

Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, Hernandez NS, Chen X, Ahmed S, Konishi K, et al: Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA. 104:18654–18659. 2007. View Article : Google Scholar : PubMed/NCBI

123 

Munro AJ, Lain S and Lane DP: P53 abnormalities and outcomes in colorectal cancer: A systematic review. Br J Cancer. 92:434–444. 2005. View Article : Google Scholar : PubMed/NCBI

124 

Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 25:1658–1664. 2007. View Article : Google Scholar : PubMed/NCBI

125 

Heinemann V, Stintzing S, Kirchner T, Boeck S and Jung A: Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 35:262–271. 2009. View Article : Google Scholar : PubMed/NCBI

126 

Boland CR: The molecular biology of gastrointestinal cancer: Implications for diagnosis and therapy. Gastrointest Endosc Clin N Am. 18:401–413. 2008. View Article : Google Scholar : PubMed/NCBI

127 

Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, Kim GP, Yothers G, Allegra C, Moore MJ, et al: DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 103:863–875. 2011. View Article : Google Scholar : PubMed/NCBI

128 

Roth AD, Delorenzi M, Tejpar S, Yan P, Klingbiel D, Fiocca R, d'Ario G, Cisar L, Labianca R, Cunningham D, et al: Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 104:1635–1646. 2012. View Article : Google Scholar : PubMed/NCBI

129 

Popat S, Hubner R and Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 23:609–618. 2005. View Article : Google Scholar : PubMed/NCBI

130 

Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M and Warusavitarne J: Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 27:1423–1431. 2012. View Article : Google Scholar : PubMed/NCBI

131 

Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 349:247–257. 2003. View Article : Google Scholar : PubMed/NCBI

132 

Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 28:3219–3226. 2010. View Article : Google Scholar : PubMed/NCBI

133 

Yang L, Sun Y, Huang XE, Yu DS, Zhou JN, Zhou X, Li DZ and Guan X: Carcinoma microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for stage II rectal cancer. Asian Pacific J Cancer Prev. 16:1545–1551. 2015. View Article : Google Scholar

134 

Tejpar S, Saridaki Z, Delorenzi M, Bosman F and Roth AD: Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: More complexity to the puzzle. J Natl Cancer Inst. 103:841–844. 2011. View Article : Google Scholar : PubMed/NCBI

135 

Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF and Uzzan B: Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 45:1890–1896. 2009. View Article : Google Scholar : PubMed/NCBI

136 

De Sousa E, Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, de Jong JH, de Boer OJ, van Leersum R, Bijlsma MF, et al: Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 19:614–618. 2013. View Article : Google Scholar : PubMed/NCBI

137 

Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, et al: A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 19:619–625. 2013. View Article : Google Scholar : PubMed/NCBI

138 

De Rosa M, Pace U, Rega D, Costabile V, Duraturo F, Izzo P and Delrio P: Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 34:1087–1096. 2015. View Article : Google Scholar : PubMed/NCBI

139 

Su S, Hu B, Shao J, Shen B, Du J, Du Y, Zhou J, Yu L, Zhang L, Chen F, et al: CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci Rep. 6:200702016. View Article : Google Scholar : PubMed/NCBI

140 

Liao Y, Chen L, Feng Y, Shen J, Gao Y, Cote G, Choy E, Harmon D, Mankin H, Hornicek F and Duan Z: Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells. Oncotarget. 8:30276–30287. 2017. View Article : Google Scholar : PubMed/NCBI

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July 2018
Volume 16 Issue 1

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
Nguyen, H.T., & Nguyen, H.T. (2018). The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review). Oncology Letters, 16, 9-18. https://doi.org/10.3892/ol.2018.8679
MLA
Nguyen, H. T., Duong, H."The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)". Oncology Letters 16.1 (2018): 9-18.
Chicago
Nguyen, H. T., Duong, H."The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)". Oncology Letters 16, no. 1 (2018): 9-18. https://doi.org/10.3892/ol.2018.8679